For many years, reversible acetylcholinesterases (AChE) have been a highly viable target for the symptomatic improvement in Alzheimer's disease (AD) because cholinergic deficit is a consistent and early finding in AD. Other brain associated and neurological disorders including myasthenia gravis have shown therapeutic response to AChE inhibition. In particular dementia symptoms (memory and language deficits) associated with AD and Parkinson's Disease have been responsive to AChE inhibitor treatments. Although all symptoms of these and other brain diseases and disorders are not fully understood, cholinergic deficit is an early and consistent finding in AD, and it is correlated with Parkinson's Disease dementia, Lewy body dementia, and vascular dementia. During healthy brain function, acetylcholine is released into the synaptic cleft, where it can bind to a post-synaptic receptor and then be split into acetate and choline. Choline can then be pumped back into the pre-synaptic terminal by its transporter to be reused for new synthesis. Keeping a steady cycle of acetylcholine in the hippocampus helps maintain memories.
There are two types of cholinesterase, AChE and butyrylcholinesterase (BuChE). AChE is primarily in the blood and neural synapses, but BuChE is primarily in the liver. The biggest difference between these two cholinesterases is the substrates: AChE breaks down acetylcholine (ACh) more quickly, while BuChE breaks down butyrylcholine (BuCh) more quickly. Brain-targeted BuChE inhibitors have been developed based on binding domain structures to help researchers understand and apply the role of this enzyme in the central nervous system. Because oral medicaments including cholinesterase-inhibiting pharmaceutical agents can include gastrointestinal side effects (nausea, vomiting, diarrhea), transdermal applications have been developed including those described in U.S. Pat. Nos. 5,391,375; 5,972,376; 6,254,883; 6,316,023; and 6,335,031; each of which is incorporated herein by reference. Intranasal administration of cholinesterase inhibitors has been experimented with and reported, but those reports are directed toward general mucosal absorption and/or targeting olfactory nerves, without delivery modalities that would target specific regions (e.g., the pterygopalatine ganglion in the pterygopalatine fossa).
Some medicaments including pharmaceutical agents that inhibit cholinesterases (e.g., galantamine, donepezil, huperzine, rivastigmine, tacrine, physostigmine) may cross the blood-brain barrier, unlike many other compounds. This provides known benefits for targeting central nervous system (CNS) tissues. However, the modes of delivery and efficacy for such therapies have not fully yet been realized.
In view of certain side effects associated with oral ingestion of AChE inhibitors and the need to target the brain for alleviating specific symptoms, it may be desirable to provide a mode of delivery that is effective for treating and at least alleviating symptoms and/or causes of one or more of seizure, stroke, Parkinson's Disease, Alzheimer's Disease, multiple sclerosis, vascular dementia, idiopathic senile dementia, multiple sclerosis, benign and cancerous brain tumors, headache, Amyotrophic Lateral Sclerosis, Adrenoleukodystrophy (ALD) (including Childhood Cerebral Adrenoleukodystrophy (CCALD)), schizophrenia, and bipolar disorder, and more particularly, it may be desirable to provide known treatment regimen of pharmaceutical agent as a secondary agent after a first agent is used to temporarily increase the permeability of the blood brain barrier of a mammal receiving treatment.